This project is a continuing series of translational clinical trials evaluating novel analgesic strategies and therapeutic agents with potential for enhanced efficacy and safety in comparison to standard treatments. Specific objectives of this project are: 1) to evaluate the analgesic potential of investigational analgesics which alter either the synthesis or receptor activation of inflammatory and neuroendocrine mediators; 2) to develop novel analgesic strategies for preventing pain and optimizing analgesia while minimizing side effect potential for acute pain in ambulatory patients; and 3) to characterize the neuroendocrine responses to surgical stress, acute pain, and inflammation. Subjects in these investigations undergo oral surgery performed with local anesthesia with resultant neuroendocrine responses to pain and surgical stress during the perioperative period as well as acute pain for several days. Samples are collected from blood to evaluate systemic responses, by microdialysis at the extraction site to measure local release of inflammatory mediators such as prostaglandins, and by tissue biopsy to measure cellular changes due to inflammation. Subjects remain at the clinic up to eight hours postoperatively and may return at 24 and 48 hours for additional observations. Results of recent studies demonstrate the efficacy of preventive strategies which decrease nociceptive input during the immediate postoperative period, have differentiated peripheral from systemic effects for prototypic analgesic drugs, and evaluated the efficacy of novel analgesic mechanisms.